Specific allergen injection immunotherapy is highly effective in selected patients with IgE-mediated disease, including respiratory allergy and venom anaphylaxis. Research in this area provides insight into the immunologic basis of allergic disease and may assist in the development of more highly targeted treatment. Immunotherapy reduces immediate allergen-induced symptoms and concentrations of inflammatory mediators, including histamine and prostaglandin D₂, in ragweed-sensitive patients. Similarly, nasal epithelial mast cell numbers are decreased. A characteristic feature of immunotherapy is its ability to inhibit late-phase responses. In the nose it is accompanied by a decrease in eosinophil numbers in lavage during late responses. Characteristic changes in serum immunoglobulins are found, with an initial increase in IgE followed by a blunting of seasonal increases in IgE in pollen-sensitive patients and a gradual decline in allergen-specific IgE levels over several years. This is accompanied by an increase in allergen-specific IgG (blocking antibodies), although neither appear to correlate closely with the clinical response to immunotherapy. One way in which immunotherapy may act is by modifying the T-lymphocyte response to subsequent natural allergen exposure. Studies in peripheral blood and within the target organ have demonstrated a shift in the balance of T-cell subsets away from T_H2-type (producing particularly IL-4 and IL-5) in favor of a T_H1-type T-lymphocyte response (with the preferential production of IFN-γ). Studies of the nasal mucosa before and after immunotherapy have demonstrated suppression of the late nasal response and increases in the numbers of cells expressing mRNA for IFN-γ. It is not clear whether this immune deviation is due to anergy of T_H2/T_H0 cells or increases in T_H0/T_H1 T-lymphocyte responses. An alternative may be amplification of suppressor CD8+ T cells, which may have a downregulatory effect. Novel approaches currently being explored include the use of T-cell reactive peptides, which might circumvent the risk of anaphylaxis, and the use of adjuvants such as IL-12 or mycobacterial vaccines to potentiate the effects of allergen in inducing immune deviation. (J Allergy Clin Immunol 1998;102:157-64.)